1. Field of Inventive Subject Matter
The present inventive subject matter relates to novel metal complex protein kinases inhibitors, methods for making such compounds, and methods for using such compounds for treating diseases and disorders mediated by kinase activity.
2. Background
The development of small molecules that perturb specific protein functions is of great importance for probing biological processes and ultimately for the development of potent and safe drugs. Medicinal chemistry is predominately focused on the design of organic molecules, whereas the incorporation of inorganic components into drugs is much less investigated. Furthermore, in almost all metallopharmaceuticals, the metal ion possesses a reactive feature. We have found that certain organometallic and inorganic compounds are useful as structural scaffolds for enzyme inhibition. Such metal-ligand assemblies allow convergent synthetic approaches and give access to structural motifs that differ from purely organic molecules. Nature makes extended use of metals not only for their reactivity but also for structural purposes, as for example in zinc binding aspartate transcarbamoylase and zinc finger domains, or the calcium binding protein calmodulin.
Protein kinases regulate most aspects of cellular life and are one of the main drug targets. An example is the microbial alkaloid staurosporine, which is a very potent, but relatively nonspecific inhibitor of many protein kinases. Many staurosporine derivatives and related organic compounds with modulated specificities have been developed and several are in clinical trials as anticancer drugs. They all share an indolo[2,3-α]carbazole aglycon which binds to the ATP binding site and can hydrogen bond with two conserved amino acids. For this class of inhibitors, specificity for a particular protein kinase can be achieved by the moiety which is attached to the indole nitrogen atoms.
Exemplary compounds and compositions in the patent database, which are claimed as protein kinase inhibitors, include the following:
U.S. Pat. No. 6,613,776, issued Sep. 2, 2003 to Knegtel, et al. discloses pyrazole compositions useful as protein kinase inhibitors, especially as inhibitors of aurora-2 and GSK-3, for treating diseases such as cancer, diabetes, and Alzheimer's disease.
U.S. Pat. No. 6,593,357, issued Jul. 15, 2003 to Green, et al. discloses pyrazole compositions useful as protein kinase inhibitors of ERK, for treating disease states in mammals that are alleviated by a protein kinase inhibitor, particularly diseases such as cancer, inflammatory disorders, restenosis, and cardiovascular disease.
U.S. Pat. No. 6,555,539, issued Apr. 29, 2003 to Reich, et al. discloses indazole compounds that modulate and/or inhibit cell proliferation, such as the activity of protein kinases, for mediating kinase-dependent diseases and treating cancer and other disease states associated with unwanted angiogenesis and/or cellular proliferation, such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, and psoriasis.
U.S. Pat. No. 6,451,838, issued Sep. 17, 2002 to Moon, et al. discloses 1-pyrrolidin-1-ylmethyl-3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives for modulating the activity of protein kinases, methods of preparing same, along with pharmaceutical compositions comprising these compounds and methods of treating diseases related to abnormal protein kinase activity utilizing pharmaceutical compositions comprising these compounds.
Thus, there is a significant need in the art for more specific and effective protein kinase inhibitors, which can be targeted to specific tissues and/or disease states. Applicants have developed metal complexes that target the ATP binding site of protein kinases. Additional ligands in the coordination sphere of the metal ion undergo additional specific contacts with other parts of the active site, giving metal complex binders with high affinity and specificity for a particular protein kinase.